Ishikawa and Barber report identification of a new component of the innate immune signaling system that recognizes and defends cells against infection by DNA and RNA viruses. The authors screened for proteins that, when expressed in human 293T cells, caused activation of an interferon-β promoter. They identified a protein they call STING (for stimulator of interferon genes). Activation of interferon gene expression in cells transfected with mouse or human versions of STING was lost in cells lacking the IκB kinase family member TBK-1 and was inhibited in cells lacking FADD (Fas-associated death domain–containing protein)—proteins known to mediate innate immune signaling. Analysis of cells from knockout mice lacking STING showed that loss of the protein increased susceptibility to viral infection. Immunoprecipitation studies with endogenous proteins showed that STING interacts with the cytoplasmic helicase RIG-1 (retinoic acid-inducible gene I), which is thought to function as a receptor that detects viral RNA. Confocal microscopy and cell fractionation both indicated that STING was found primarily in the endoplasmic reticulum. A yeast two-hybrid screen to identify binding partners for STING identified TRAPβ (translocon-associated protein subunit β, also called SSR2 or signal sequence receptor 2), a protein that functions in movement of newly translated proteins into the endoplasmic reticulum. The authors propose that RIG-I may detect translating viral RNAs at the endoplasmic reticulum and generate signals through interaction with STING that promote expression of type I interferons to defend against viral infection.